Cardiovascular diseases related to lipid metabolism disorders are very frequent in the industrialised countries. In Italy, for instance, they account for more than 40% of the overall mortality (Capocaccia R., Farchi G., Prati S. et al.: La mortalita' in Italia nell'anno 1989. Rapporto ISTISAN 1992/22). Our knowledge of the relationships between cholesterol and coronary heart disease stems from epidemiological studies conducted in recent years. The conclusions of these studies indicate that the development of severe coronary atherosclerosis is closely related to serum cholesterol levels (McGill H. C. Jr. et al.: The International Atherosclerosis Project. Lab. Invest. 18: 463-653, 1968; Keys A.: Seven Countries: Death and Coronary Heart Disease. Harvard University Press, Cambridge, 1980).
Correction of eating habits through an appropriate diet is always the first measure to be adopted in cases of hyperlipidaemia. Good results, however, are not always achieved owing to widespread intolerance of the strict dietary regimen, to the severity of the hypercholesterolaemia or to genetic-type resistance.
In these cases, to achieve the desired results, that is to say to restore normal blood levels of triglycerides and cholesterol, it proves necessary to resort to pharmacological treatment with lipid-lowering drugs. This category includes both drugs that prevalently reduce cholesterol levels and drugs that prevalently reduce triglyceride levels.
The former group of drugs includes statins, probucol and resins, and the latter group fibrates, nicotinic acid and omega-3-series fatty acids.
The statins (simvastatin, lovastatin, pravastatin, fluvastatin and the like) are hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. By inhibiting this enzyme, they reduce the hepatic synthesis of cholesterol (Lancet 1994; 334: 1383-1389). To compensate for the reduction in intracellular cholesterol, the liver cell produces more receptors for lipoproteins of the LDL and VLDL series, which in this way are removed from the bloodstream.
In addition, the statins cause less absorption of cholesterol of dietary origin in the intestine and a reduced output of apoprotein B present in low-density lipoproteins (LDL).
The statins are better tolerated than the other cholesterol-lowering agents, but present certain drawbacks: the most common side effects caused by these drugs are gastrointestinal disorders, skin rashes and headache.
A number of patients have complained of sleep disorders (E J Schaffer, N Engl J Med, 319:1222,1988; Lancet, 339:547, Feb. 29, 1992), while significant increases in transaminase activity (GOT and GPT) and in CK compared to basal values have been observed in patients taking statins in doses of 40 mg/kg (Schweiz Med Wochenschr Jun. 29, 1991; 121 (26): 977-83).
Moreover, patients treated with simvastatin present side effects related to myopathy, rhabdomyolysis, muscle pain and increases in serum CK and LDH activity [Dedlypere J. P. & Vermeulen A. (1991) Ann. Intern. Med. 114:342; Bizzarro N. et al. (1992) Clin. Chem. 38: 1504].
EP 0383432 describes the combination of an HMG-CoA reductase inhibitor and coenzyme Q10 for the treatment of skeletal muscle myopathy caused by statins.
It has been reported that statins cause a reduction in the number of deaths due to coronary heart disease, but, on the other hand, an increase in deaths due to other events such as tumours or trauma has been noted in treated patients (Davey-Smith G., Song F., Sheldon T. A., Cholesterol lowering and mortality: the importance of considering initial level at risk. BMJ 1993; 306: 1367-1373; Ravnshov U.; Cholesterol lowering trials in coronary heart disease: frequency of citation and outcome. BMJ 1992; 305: 15-19). Young rats treated with different cholesterol-lowering agents (simvastatin, lovastatin, and pravastatin) show signs of myopathy, when high doses of simvastatin are used (Reijneveld J. C. et al., 1976 Pediatr. Res. 39: 1028-1035). Moreover, Bhuiyan et al. (Bhuiyan J. & Seccombe D. W. 1996 Lipids 31: 867-870) have demonstrated that the administration of lovastatin to rabbits causes a significant reduction in hepatic, cardiac and skeletal muscle L-carnitine.
The results of experiments in animals and in human subjects have suggested that, to reduce cholesterol levels, pharmacological treatment with statins should be used only in patients at high risk of coronary disease in the short term (JAMA, 1996; 275: 55-60).
Equally well known are the triglyceride- and cholesterol-lowering effects of a number of alkanoyl carnitines, in particular of acetyl L-carnitine. U.S. Pat. No. 4,268,524 describes a therapeutic method for increasing the level of high-density lipoproteins (HDL) so as to selectively reduce the LDL+VLDL:HDL ratio in the plasma of patients at risk of cardiovascular disease, in whom this ratio is abnormally high, This method includes the daily administration of 5-50 mg/kg of alkanoyl carnitine or of one of its pharmacologically acceptable salts.
The international patent application WO99/01126 filed in the name of the applicant describes the use of alkanoyl L-carnitine in combination with statins for the treatment of diseases related to lipid metabolism disorders. WO99/01126 does not describe or suggest that L-carnitine or the alkanoyl L-carnitines exert a protective action on statin-induced toxic or side effects.